© 1989 Oxford University Press
research-article |
Atropine and/or Diazepam Therapy Protects against Soman-Induced Neural and Cardiac Pathology1
Behavioral Toxicology Branch, U.S. Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground, Maryland 21010-5425 *Comparative Pathology Branch, U.S. Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground, Maryland 21010-5425
Received December 22, 1987; accepted January 10, 1989
Toxic doses of the organophosphonate anticholinesterase agent soman can produce neural and cardiac lesions in animals that survive the acute poisoning. The ability of two standard antidote drugs, atropine and diazepam. along with the oxime pralidoxime (2-PAM) Cl, were evaluated for their ability to block these pathological effects. Rats were challenged with a fixed dose (85 µkg, sc) of soman and treated im 5 min later with 25 mg/kg 2-PAM CI and one of the following combinations of atropine (0.0, 1.0, 3.2, 10.0, or 32.0 mg/kg) and diazepam (0.0, 0.1, 0.32, 1.0, or 3.2 mg/kg) in a balanced design. The severity of acute anticholinesterase intoxication signs was rated 1 hr after exposure. My weights and behavioral reactivity ratings were obtained daily for 16 days after exposure; brains and hearts of all surviving subjects were then evaluated for pathological changes. Soman challenge resulted in 33% lethality in animals that received only 2-PAM therapy; both atropine and diazepam reduced lethality in a dose-dependent fashion. Across all treatment conditions >50% of the deaths occurred later than 24 hr after intoxication and treatment. Acute intoxication signs were differentially moderated by the two drugs. atropine reduced all six signs in a dose-dependent fashion; diazepam had no effect on lacrimation and eye bulb protrusion, antagonized signs of salivation and motor abnormalities in a dose-dependent manner, and antagonized the effects of soman on signs of physical activity and coordination only at low doses. All doses of diazepam and the highest dose of atropine moderated body weight loss and a syndrome of behavioral hyperreactivity observed after exposure. Brain pathology was significantly reduced by all doses of diazepam and/or the highest dose of atropine, but no single drug or drug combination was effective in protecting all animals in a group from some brain pathology. Both drugs blocked the development of cardiac lesions in a dose-dependent fashion. The results demonstrate that diazepam or high doses of atropine can antagonize the development of brain lesions that result from soman exposure. Pharmacological management of epileptiform motor abnormalities during the acute intoxication is critical for this effect. In contrast, soman-induced cardiac pathology may occur secondarily as a consequence of the severe brain lesions or develop independently of brain lesion formation due possibly to sympathetic overstimulation.